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United States Patent |
5,663,191
|
Lavielle
,   et al.
|
September 2, 1997
|
Benzopyran compounds as 5HT.sub.2C receptor antagonists
Abstract
Compounds of formula (I):
##STR1##
in which: n represents 1 or 2,
R.sub.1 represents hydrogen or alkyl, benzyl, acetyl, benzoyl, allyl,
pyridinecarbonyl, pyridinemethyl, acylaminoalkyl (optionally substituted),
pyridineaminocarbonyl, phthalimidoalkyl, thiochromanyloxyalkyl or
(benzodioxanyloxy)alkyl,
R.sub.2, R.sub.3 or R.sub.4, which may be identical or different, represent
hydrogen or halogen or alkyl, alkoxy, hydroxyl, acetyl, aminocarbonyl,
aminomethyl, cyano, nitro, amino, phenyl (which may or may not be
substituted), furyl, pyridinyl, thienyl or pyridyl, or alternatively,
when they are located on adjacent carbons, R.sub.2 and R.sub.3 form, with
the carbon atoms which bear them, a furan or phenyl ring,
the isomers thereof and the addition salts thereof with a pharmaceutically
acceptable acid, and medicinal products containing the same are useful for
the treatment of diseases requiring a ligand to the 5-HT.sub.2C receptors.
Inventors:
|
Lavielle; Gilbert (La Celle Saint Cloud, FR);
Dubuffet; Thierry (L'Hay Les Roses, FR);
Millan; Mark (Paris, FR);
Newman-Tancredi; Adrian (Le Pecq, FR)
|
Assignee:
|
Adir Et Compagnie (Courbevoie, FR)
|
Appl. No.:
|
498217 |
Filed:
|
July 5, 1995 |
Foreign Application Priority Data
Current U.S. Class: |
514/411; 514/338; 546/276.7; 548/430 |
Intern'l Class: |
A61K 031/40; C07D 491/052 |
Field of Search: |
514/411,291,338
546/89,276.7
548/430
|
References Cited
U.S. Patent Documents
4666916 | May., 1987 | Schneider | 514/291.
|
Other References
Forbes IT, Kennet GA, Gadre A, Ham P, Hayward CJ, Martin RT, Thompson M,
Wood, MD, Baxter GS, Glen A, Murphy OE, Stewart BA, Blackburn TP. J. Med.
Chem. 36, 1104-1107. 1993.
Wood MD, Glen A, Murphy O, Stewart BR, Blackburn TP. Brit. J. Pharmacol.
111, 144P. Jan. 1994.
|
Primary Examiner: Ivy; C. Warren
Assistant Examiner: Huang; Evelyn
Attorney, Agent or Firm: The Firm of Gordon W. Hueschen
Claims
We claim:
1. A compound selected from those of formula (I):
##STR23##
in which: n represents 1,
R.sub.1 represents hydrogen, linear or branched (C.sub.1 -C.sub.6) alkyl,
benzyl, acetyl, benzoyl, allyl, pyridinecarbonyl, pyridinemethyl,
pyridineaminocarbonyl, linear or branched (C.sub.1 -C.sub.6)
phthalimidoalkyl, linear or branched (C.sub.1 -C.sub.4)
(thiochroman-8-yloxy)alkyl, linear or branched (C.sub.1 -C.sub.4)
(benzodioxanyloxy)alkyl, or linear or branched (C.sub.1 -C.sub.6)
acylaminoalkyl wherein acyl is benzoyl, naphthylcarbonyl, thienylcarbonyl,
linear or branched (C.sub.1 -C.sub.6) alkylcarbonyl, furylcarbonyl,
pyrrolylcarbonyl, pyridinylcarbonyl, or (C.sub.3 -C.sub.7)
cycloalkylcarbonyl, each of these acyl groups being optionally substituted
with one or more halogen, trihalomethyl, alkoxy or hydroxyl,
R.sub.2, R.sub.3 or R.sub.4, which may be identical and different,
represent hydrogen, halogen, linear or branched (C.sub.1 -C.sub.6) alkyl,
linear or branched (C.sub.1 -C.sub.6) alkoxy, hydroxyl, acetyl,
aminocarbonyl, aminomethyl, cyano, nitro, amino, phenyl which may or may
not be substituted with one or more halogen, hydroxyl, linear or branched
(C.sub.1 -C.sub.6) alkoxy, linear or branched (C.sub.1 -C.sub.6) alkyl, or
trihalomethyl, or R.sub.2, R.sub.3, and R.sub.4 represent furyl,
pyridinyl, thienyl or pyrrolyl,
the optical isomers thereof and the addition salts thereof with a
pharmaceutically-acceptable acid.
2. A compound of claim 1, in which R.sub.1 represents a benzyl group, the
optical isomers thereof and the addition salts thereof with a
pharmaceutically-acceptable acid.
3. A compound of claim 1, in which at least one of the groups R.sub.2,
R.sub.3 and R.sub.4 represents a linear or branched (C.sub.1 -C.sub.6)
alkoxy group or a hydroxyl group, the optical isomers thereof and the
addition salts thereof with a pharmaceutically-acceptable acid.
4. A method for treating a living animal body afflicted with a condition
requiring an antagonist of the 5-HT.sub.2C receptors comprising the step
of administering to the living body an amount of a compound of claim 1
which is effective for alleviation of said condition.
5. A pharmaceutical composition comprising as active principle an effective
5-HT.sub.2C receptor antagonistic amount of a compound as claimed in claim
1, together with one or more pharmaceutically-acceptable excipients or
vehicles.
6. A compound of claim 1 selected from the group consisting of
trans-2-[3-(4-fluorobenzoylamino)ethyl]-9-methoxy-1,3,3a,4,9b-pentahydro-(1
)-benzopyrano[3,4-c]pyrrole;
trans-2-benzyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le hydrochloride;
trans-2-benzyl-7-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrol
e hydrochloride; and
trans-2-benzyl-8-cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride.
7. A method of claim 4 wherein the compound is selected from the group
consisting of:
trans-2-[3-(4-fluorobenzoylamino)ethyl]-9-methoxy-1,3,3a,4,9b-pentahydro-(1
)-benzopyrano[3,4-c]pyrrole;
trans-2-benzyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le hydrochloride;
trans-2-benzyl-7-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrol
e hydrochloride; and
trans-2-benzyl-8-cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride.
8. A composition of claim 5 wherein the compound is selected from the group
consisting of:
trans-2-[3-(4-fluorobenzoylamino)ethyl]-9-methoxy-1,3,3a,4,9b-pentahydro-(1
)-benzopyrano[3,4-c]pyrrole;
trans-2-benzyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le hydrochloride;
trans-2-benzyl-7-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrol
e hydrochloride; and
trans-2-benzyl-8-cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride.
Description
BACKGROUND OF THE INVENTION--PRIOR ART
Besides the fact that they are novel, the compounds of the present
invention have particularly advantageous properties by selectively binding
to the 5-HT.sub.2C serotoninergic receptors with respect to the
5-HT.sub.2A receptors. This novel property has never been demonstrated for
the most closely related compounds of the prior art such as, for example,
those described in patents WO 9006927, EP 410,535, EP 539,209 or EP 95666.
FIELD OF THE INVENTION
It is well established that the ascending serotoninergic, dopaminergic and
adrenergic pathways projecting towards the limbic system and the cortex
play a deciding role in controlling mood and in the etiology and treatment
of psychiatric diseases such as schizophrenia, depression and anxiety, as
well as aggression and other impulse disorders (M. J. Millan et al., Drug
News & Perspectives, 5, 397-406, 1992; A. Y. Dentch et at., Schizophrenia,
4, 121-156, 1991; H. Y. Meltzer and J. F. Nash, Pharmacol. Rev., 43,
587-604, 1991). These pathways express their actions by a multitude of
different receptors, and increasingly greater efforts are being made in
order to identify the types of receptors involved in these diseases. It is
thus hoped that by modifying their activity with agonists or antagonists,
correction of disorders reflecting dysfunction of the monoaminergic
systems may be achieved.
As regards serotonin (5-HT), at least 7 different types of receptors have
been cloned, although present understanding at the functional level is
fairly limited for several of them. Nevertheless, for the two subtypes of
5-HT.sub.2 receptors which are present in the brain, 5-HT.sub.2A and
5-HT.sub.2C, good indications exist that they are more particularly
involved in controlling mood (J. F. W. Deakin, Pharmacol. Biochem. Behav.,
29, 819-820, 1988) as well as in the modulation of several physiological
functions such as the appetite (G. A. Kennett et at., Eur. J. Pharmacol.,
164, 445-454, 1989), sleep (C. Dugovic et at., Psychopharmacology, 97,
436-442, 1989), sexual behavior (H. H. G. Berendsen et at.,
Psychopharmacology, 101, 57-61, 1990), motor activity (G. A. Kennett and
G. Curzon, Psychopharmacology, 96, 93-100, 1988) and cardiovascular
functioning (I. K. Anderson et at., Br. J. Pharmacol., 107, 1020-1028,
1992). Consequently, in animals, activation of the 5-HT.sub.2C receptors
appears to bring about, for example, a decrease in the motor activity (I.
Lucki et at., J. Pharmacol. Exp. Ther., 249, 155-164, 1989) and a
reduction in food intake (S. J. Kitchener and C. T. Dourish,
Psychopharmacology, 113, 369-377, 1994), whereas in animals or in man,
antagonism of the 5-HT.sub.2A/2C receptors is associated with anxiolytic
effects (G. A. Kennet et at., Eur. J. Pharmacol., 164, 445-454, 1989, D.
L. S. Ceuleumans et al., Pharmacopsychiatry, 18, 303-305, 1985),
antidepressant effects (F. Jenck et al., Eur. J. Pharmacol., 321, 223-229,
1993) and anti-schizophrenic effects (D. L. S. Ceuleumans et al., J.
Pharmacol. Exp. Ther., 85, 329-332, 1985). Moreover, blocking of the
5-HT.sub.2A/2C receptors appears to be involved in the atypical profile of
the antipsychotic agent clozapine (A. Y. Deutch et al., Schizophrenia, 4,
121-156, 1991).
In view of their very great similarity, it has been extremely difficult to
differentiate between the actions induced by the 5-HT.sub.2A receptors and
those of the 5-HT.sub.2C receptors. Furthermore, for a long time, no
antagonist existed which was selectively interactive with 5-HT.sub.2A
receptors or with the 5-HT.sub.2C receptors. Thus, the recent discovery of
a selective 5-HT.sub.2A antagonist, MDL 100,907, and of a selective
5-HT.sub.2C antagonist, SB 200,646, has aroused much interest (Sorensen et
al., J. Pharmacol. Exp. Ther., 1993). The first results obtained with the
compound SB 200,646 showing its anxiolytic properties allow a particularly
important role of the 5-HT.sub.2C receptors to be envisaged in controlling
mood (G. A. Kennett et al., Br. J. Pharmacol., 111, 797-802, 1994; G. A.
Kennett et al., Eur. J. Pharmacol., 164, 445-454, 1989). This conviction
is strongly reinforced by the clinical results obtained with mCPP, which
behaves as a 5-HT.sub.2C agonist and a 5-HT.sub.2A antagonist (G. A.
Kennett and G. Curzon, Br. J. Pharmacol., 94, 137-147, 1988; I. Lucki et
al., J. Pharmacol. Exp. Ther., 249, 155-164, 1989; P. J. Conn and E.
Sanders-Bush, J. Pharmacol. Exp. Ther., 242, 552-557, 1987), which
possesses pronounced, anxiogenic properties and which exacerbates
depressive, aggressive and psychotic states in patients (D. L. Murphy et
al., Psychopharmacology, 98, 275-282, 1989; J. H. Krystal et al., Soc.
Neurosci. Abst., 17, 354, 1991; J. P. Seibyl, Soc. Neurosci. Abst., 15,
1236, 1989).
The compounds described in the present invention bind selectively to the
5-HT.sub.2C receptors with respect to the 5-HT.sub.2A receptors and are
antagonists which may thus be used in the treatment of diseases such as
anxiety, depression, impulse disorders (such as aggression, B. A.
McMillen, Drug. Develop. Persp., 12, 53-62, 1988), schizophrenia, appetite
disorders (such as anorexia), cardiovascular diseases, sexual dysfunction
(H. H. G. Berendsen et al., Psychopharmacology, 101, 57-61, 1990),
cerebral ischemic attacks (F. Granier et al., Acta Psychiatr. Stand., 72,
67-74, 1985; W. D. Dietrich et al., J. Cereb. Blood Flow Metabol., 9,
812-820, 1989; J. A. Zivin, Neurology, 34, 469-474, 1984; J. A. Zivin,
Neurology, 35, 584-587, 1985; K. M. Bode-Greuel et al., Stroke, 21,
164-166, 1990), drug abuse (T. F. Meert and P. A. J. Janssen, Drug.
Develop. Res., 25, 39-53, 1992; T. F. Meert and P. A. J. Janssen, Drug.
Develop. Res., 25, 55-66, 1992; E. M. Sellers et al., Trends Pharmacol.
Sci., 13, 69-75, 1992), sleeping disorders (C. Dugovic et al.,
Psychopharmacology, 97, 436-442, 1989) and migraine (D. L. Murphy et al.,
Psychopharmacology, 98, 275-282, 1989).
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to the compounds of
formula (I):
##STR2##
in which: n represents 1 or 2,
R.sub.1 represents a hydrogen atom or a linear or branched (C.sub.1
-C.sub.6) alkyl group, a benzyl, acetyl, benzoyl, allyl, pyridinecarbonyl
or pyridinemethyl group, a pyridineaminocarbonyl group, a linear or
branched (C.sub.1 -C.sub.6) phthalimidoalkyl group, a linear or branched
(C.sub.1 -C.sub.4) (thiochroman-8-yloxy)alkyl group, a linear or branched
(C.sub.1 -C.sub.4) (benzodioxanyloxy)alkyl group or a linear or branched
(C.sub.1 -C.sub.6) acylaminoalkyl group, (wherein acyl is a benzoyl group,
a naphtylcarbonyl group, a thienylcarbonyl group, a linear or branched
(C.sub.1 -C.sub.6) alkylcarbonyl group, a furylcarbonyl group, a
pyrrolylcarbonyl group, a pyridinylcarbonyl group, or a (C.sub.3 -C.sub.7)
cycloalkylcarbonyl group, each of these groups being optionally
substituted with one or more halogen atoms, trihalomethyl group, alkoxy
group or hydroxy group),
R.sub.2, R.sub.3 or R.sub.4, which may be identical or different, represent
a hydrogen or halogen atom or a linear or branched (C.sub.1 -C.sub.6)
alkyl group, a linear or branched (C.sub.1 -C.sub.6) alkoxy group, a
hydroxyl, acetyl, aminocarbonyl, aminomethyl, cyano, nitro or amino group,
a phenyl group (which may or may not be substituted with one or more
halogen atoms or hydroxyl groups, linear or branched (C.sub.1 -C.sub.6)
alkoxy groups, linear or branched (C.sub.1 -C.sub.6) alkyl groups or
trihalomethyl groups), a furyl group, a pyridinyl group, a thienyl group
or a pyrrolyl group, or alternatively, when they are located on adjacent
carbons, R.sub.2 and R.sub.3 form, with the carbon atoms which bear them,
a furan or phenyl ring,
the isomers thereof and the addition salts thereof with a pharmaceutically
acceptable acid.
Among the pharmaceutically acceptable acids which may be mentioned, without
any limitation, are hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic
acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric
acid, maleic acid, citric acid, ascorbic acid, oxalic acid,
methanesulfonic acid, camphoric acid, etc.
The invention also relates to the process for the preparation of the
compounds of formula (I). In this process, when the compounds of formula
(I) which it is desired to obtain are such that n=1, a pyrrolidine of
formula (II) is used as starting material, in the form of a pair of
enantiomers or a pure enantiomer:
##STR3##
in which R.sub.2, R.sub.3 and R.sub.4 are as defined in formula (I), which
compound of formula (II), when it is in the form of a pair of enantiomers,
is reacted with lithium aluminum hydride in an inert solvent to give the
pyrrolidine of formula (III):
##STR4##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I),
the methoxy function of which is converted into a hydroxyl function by
reaction in the presence of sodium thioethoxide or boron tribromide, and
which is then reacted with gaseous hydrogen chloride in the presence of
thionyl chloride, in chloroform medium, to give the compound of formula
(IV):
##STR5##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I),
which compound is then cyclized in basic medium,
to give the compound of formula (I/a), a particular case of the compounds
of formula (I):
##STR6##
in which R.sub.2, R.sub.3 or R.sub.4 have the same meaning as in formula
(I),
compound of formula (I/a), the amine function of which may be deprotected,
if so desired, by catalytic hydrogenation,
to give the compound of formula (I/b), a particular case of the compounds
of formula (I):
##STR7##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I), which compound of formula (I/b) may be reacted, if so desired, with a
halo derivative:
R'.sub.1 X
in which:
X represents a halogen atom and
R'.sub.1 represents a linear or branched (C.sub.1 -C.sub.6) alkyl group, an
acetyl, benzoyl, pyridinecarbonyl, pyridinemethyl or
3-pyridineaminocarbonyl group or a linear or branched (C.sub.1 -C.sub.6)
phthalimidoalkyl group,
to give
either the compound of formula (I/c), a particular case of the compounds of
formula (I):
##STR8##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I) and R".sub.1 represents a linear or branched (C.sub.1 -C.sub.6) alkyl
group, an acetyl, benzoyl, pyridinecarbonyl, pyridinemethyl or
3-pyridineaminocarbonyl group or a linear or branched (C.sub.1 -C.sub.6)
phthalimidoalkyl group,
or the compound of formula (V):
##STR9##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I) and alkCN represents a linear or branched (C.sub.1 -C.sub.6)
cyanoalkyl group, compound of formula (V), the cyano group of which is
reduced to an amino group and which is reacted with a benzoyl halide
(optionally substituted with a halogen atom),
to give the compound of formula (I/d), a particular case of the compounds
of formula (I):
##STR10##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I) and R"'.sub.1 represents a linear or branched (C.sub.1 -C.sub.6)
benzoylaminoalkyl group (optionally substituted on the phenyl ring with a
halogen atom),
which compound of formula (I/a), (I/b), (I/c) or (I/d):
is optionally purified according to a standard purification technique,
whose enantiomers are separated, if so desired, according to a standard
separation technique,
and which is converted, where appropriate, into the addition salts thereof
with a pharmaceutically acceptable acid,
it being understood that the substituents R.sub.2, R.sub.3 and R.sub.4 may
be introduced or modified throughout the synthesis of the compounds of
formula (I), according to standard techniques in organic chemistry.
The compounds of formula (II) used as starting materials are prepared
according to the process described by K. Achiwa et al. (Chem. Pharm.
Bull., 33(7), 2762-2766, 1985) by performing a cycloaddition of an
ethylene of formula (IIa):
##STR11##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I),
with N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine in the presence of
a catalyst such as trifluoroacetic acid. Depending on the configuration of
the ethylene of formula (IIa) used, this cycloaddition gives a pyrrolidine
of formula (II) in which the hydrogen atoms located in positions 3 and 4
are cis or trans relative to each other.
The compounds of formula (IV) may also be obtained, when the pyrrolidine
possesses hydrogen atoms in a cis position relative to each other, by
performing a cycloaddition according to the process described by K. Achiwa
et al. (cited above) of a coumarin of formula (VI):
##STR12##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I),
with N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine, using
trifluoroacetic acid as catalyst,
to give the compound of formula (VII):
##STR13##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I), which compound then undergoes a reduction in the presence of lithium
aluminum hydride,
to give the compound of formula (VIII):
##STR14##
which is reacted with gaseous hydrogen chloride in the presence of thionyl
chloride,
to give the compound of formula (IV).
In the process for the preparation of the compounds of formula (I), for
which n=2, the starting material used is the compound of formula (IX):
##STR15##
in which R.sub.2, R.sub.3 and R.sub.4 are as defined in formula (I), which
compound is reacted, according to the method described in Can. J. Chem.,
52, 2316, 1974, with methylmagnesium bromide and then with
p-toluenesulfonic acid,
to give the compound of formula (X):
##STR16##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I), which compound is reacted with benzylamine in the presence of
formaldehyde,
to give the compound of formula (XI):
##STR17##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I),
which compound then undergoes a catalytic hydrogenation to give the
compound of formula (I/e), a particular case of the compounds of formula
(I):
##STR18##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I),
which compound of formula (I/e) may be reacted, if so desired, with a halo
derivative of formula (XII):
R'.sub.1A --X (XII)
in which:
X represents a halogen atom and
R'.sub.1A represents a linear or branched (C.sub.1 -C.sub.6) alkyl group,
an acetyl, benzoyl, benzyl, pyridinecarbonyl, pyridinemethyl or
3-pyridineaminocarbonyl group or a linear or branched (C.sub.1 -C.sub.6)
phthalimidoalkyl group,
to give
either the compound of formula (I/f), a particular case of the compounds of
formula (I):
##STR19##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I) and R".sub.1A represents a linear or branched (C.sub.1 -C.sub.6) alkyl
group, an acetyl, benzoyl, benzyl, pyridinecarbonyl, pyridinemethyl or
3-pyridineaminocarbonyl group or a linear or branched (C.sub.1 -C.sub.6)
phthalimidoalkyl group,
or the compound of formula (XIII):
##STR20##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I) and alkCN represents a linear or branched (C.sub.1 -C.sub.6)
cyanoalkyl group
compound of formula (XIII), the cyano group of which is reduced to an amine
group and which is reacted with a benzoyl halide (optionally substituted
with a halogen atom),
to give the compound of formula (I/g), a particular case of the compounds
of formula (I):
##STR21##
in which R.sub.2, R.sub.3 and R.sub.4 have the same meaning as in formula
(I) and R"'.sub.1 represents a linear or branched (C.sub.1 -C.sub.6)
benzoylaminoalkyl group (optionally substituted on the phenyl ring with a
halogen atom),
which compound of formula (I/e), (I/f) or (I/g):
is optionally purified according to a standard purification technique,
whose enantiomers are separated, if so desired, according to a standard
separation technique,
and which is converted, where appropriate, into the addition salts thereof
with a pharmaceutically acceptable acid,
it being understood that the substituents R.sub.2, R.sub.3 and R.sub.4 may
be introduced or modified throughout the synthesis of the compounds of
formula (I), according to standard techniques in organic chemistry.
Another subject of the present invention is the pharmaceutical compositions
containing, as active principle, at least one compound of formula (I)
alone or in combination with one or more inert, non-toxic excipients or
vehicles.
Among the pharmaceutical compositions according to the invention, there may
more particularly be mentioned those which are suitable for oral,
parenteral and nasal administration, simple or coated tablets, sublingual
tablets, gelatin capsules, lozenges, suppositories, creams, ointments,
dermal gels, etc.
The appropriate dosage varies depending on the age and weight of the
patient, the nature and severity of the complaint and the route of
administration. The latter may be an oral, nasal, rectal or parenteral
route. In general, the unit dosage ranges between 1 and 500 mg for a
treatment of 1 to 3 doses taken per 24 hours.
The examples which follow illustrate the invention and do not limit it in
any way.
The structures of the compounds described in the examples were confirmed by
the usual spectroscopic techniques.
The position of the hydrogen atoms located between the two heterocycles is
indicated in the following way:
##STR22##
The preparations described below lead to starting materials used during the
synthesis of the compounds of the invention.
Preparation A: Methyl
[trans-1-benzyl-4-(2-methoxyphenyl)pyrrolidin-3-yl]carboxylate
The expected product is obtained according to the process described by K.
Achiwa et al. (Chem. Pharm. Bull., 33(7), 2762-2766, 1985). To a solution
containing 120 mmol of methyl trans-(2-methoxy)cinnamate and 0.1 ml of
trifluoroacetic acid in 150 ml of ethyl acetate cooled to 5.degree. C.,
are slowly added 100 mmol of
N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine. The reaction medium
is brought from 30.degree. C. to 55.degree. C. over 75 minutes. 0.75 g of
potassium carbonate is then added and the mixture is kept stirring for 15
minutes. After filtration and evaporation of the solvents, the residue is
taken up in 100 ml of ethyl acetate and the solution is brought to 50)C.
110 mmol of oxalic acid dissolved in 100 ml of acetone are then added with
vigorous stirring. The stirring is continued for 15 hours. The expected
product in the form of the oxalate is then obtained after filtration, and
is rinsed with ether. The base is obtained after treatment of the oxalate
with two equivalents of 1N potassium hydroxide.
Infrared: .nu..sub.CO (nujol)=1736 cm.sup.-1
Preparation B:
Methyl[trans-1-benzyl-4-(2,6-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate
The expected product is obtained according to the process described in
Preparation A, using methyl trans-(2,6-dimethoxy)cinnamate as starting
material.
Infrared: .nu..sub.CO (nujol)=1736 cm.sup.-1
Preparation C:
Methyl[trans-1-benzyl-4-(2,5-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate
The expected product is obtained according to the process described in
Preparation A, using methyl trans-(2,5-dimethoxy)cinnamate as starting
material.
Infrared: .nu..sub.CO (nujol)=1736 cm.sup.-1
Preparation D:
cis-2-Benzyl-1,3,3a,9b-tetrahydrobenzopyrano[3,4-c]pyrrol-4-one
The expected product is obtained according to the process described in
Preparation A, using coumarin as starting material.
Melting point (oxalate): 170.degree.-175.degree. C.
Preparation E:
Methyl[cis-1-benzyl-4-(2,6-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate
The expected product is obtained according to the process described in
Preparation A, using methyl cis-(2,6-dimethoxy)cinnamate as starting
material.
Infrared: .nu..sub.CO (nujol)=1757 cm.sup.-1
Preparation F:
Methyl[trans-1-benzyl-4-(2-methoxy-4-chlorophenyl)pyrrolidin-3-yl]carboxyl
ate
The expected product is obtained according to the process described in
Preparation A, using methyl trans-(2-methoxy-4-chloro)cinnamate as
starting material.
Infrared: .nu..sub.CO (nujol)=1755 cm.sup.-1
Preparation G: cis-2-Benzyl-7-methoxy-1,3,3a,9b-tetrahydrobenzopyrano
[3,4-c]pyrrol-4-one
The expected product is obtained according to the process described in
Preparation A, using 7-methoxycoumarin as starting material.
Melting point (oxalate): 182.degree.-186.degree. C.
Preparation H:
Methyl[trans-1-benzyl-4-(2,4-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate
The expected product is obtained according to the process described in
Preparation A, using methyl trans-(2,4-dimethoxy)cinnamate as starting
material.
Preparation I:
Methyl[trans-1-benzyl-4-(2,3-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate
The expected product is obtained according to the process described in
Preparation A, using methyl trans-(2,3-dimethoxy)cinnamate as starting
material.
Preparation J:
cis-2-Benzyl-8-chloro-1,3,3a,9b-tetrahydrobenzopyrano[3,4-c]pyrrol-4-one
The expected product is obtained according to the process described in
Preparation A, using 6-chlorocoumarin as starting material.
Melting point (oxalate): 197.degree. C.
Preparation K:
Methyl[trans-1-benzyl-4-(2-methoxy-5-chlorophenyl)pyrrolidin-3-yl]carboxyl
ate
The expected product is obtained according to the process described in
Preparation A, using methyl trans-(2-methoxy-5-chloro)cinnamate as
starting material.
Melting point (oxalate): 144.degree. C.
Preparation L:
cis-2-Benzyl-6-chloro-1,3,3a,9b-tetrahydrobenzopyrano[3,4-c]pyrrol-4-one
The expected product is obtained according to the process described in
Preparation A, using 8-chlorocoumarin as starting material.
Preparation M:
Methyl[trans-1-benzyl-4-(2-methoxy-3-chlorophenyl)pyrrolidin-3-yl]carboxyl
ate
The expected product is obtained according to the process described in
Preparation A, using methyl trans-(2-methoxy-3-chloro)cinnamate as
starting material.
Preparation N:
Methyl[trans-1-benzyl-4-(2-methoxy-5-bromophenyl)pyrrolidin-3-yl]carboxyla
te
The expected product is obtained according to the process described in
Preparation A, using methyl trans-(2-methoxy-5-bromo)cinnamate as starting
material.
Preparation O:
Methyl[trans-1-benzyl-4-(2-methoxynaphth-1-yl)pyrrolidin-3-yl]carboxylate
The expected product is obtained according to the process described in
Preparation A, using methyl trans-3-(2-methoxynaphth-1-yl)acrylate as
starting material.
Preparation P:
Methyl[trans-1-benzyl-4-(1-methoxynaphth-2-yl)pyrrolidin-3-yl]carboxylate
The expected product is obtained according to the process described in
Preparation A, using methyl trans-3-(1-methoxynaphth-1-yl)acrylate as
starting material.
Preparation Q:
cis-16-Benzyl-13,14,15,17-tetrahydro-11-oxa-12-one-16-azacyclopenta[a]phen
anthrene
The expected product is obtained according to the process described in
Preparation A, using benzo[h]chroman-2-one as starting material.
Preparation R:
cis-2-Benzyl-1,3,3a,11c-pentahydro-4-one-5-oxa-2-azacyclopenta[c]phenanthr
ene
The expected product is obtained according to the process described in
Preparation A, using benzo[f]chromen-3-one as starting material.
EXAMPLE 1
trans-2-Benzyl-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
Stage A: trans-1-Benzyl-3-hydroxymethyl-4-(2-methoxyphenyl)pyrrolidine
To 560 mmol of lithium aluminum hydride in 800 ml of tetrahydrofuran (THF),
under a nitrogen atmosphere and at 5.degree. C., are added 225 mmol of
methyl [trans-1-benzyl-4-(2-methoxyphenyl)pyrrolidin-3-yl]carboxylate
(described in Preparation A) dissolved in 500 ml of THF. After stirring
for 1 hour at 5.degree. C., 139 ml of isopropyl alcohol are added slowly
to the above mixture, followed by 85.2 ml of saturated sodium chloride
solution. The mixture is stirred slowly at room temperature. After
filtration and evaporation of the solvents, the expected product is
obtained.
Stage B: trans-1-Benzyl-3-hydroxymethyl-4-(2-hydroxyphenyl)pyrrolidine
To a previously prepared solution containing 96 mmol of sodium thioethoxide
in 140 ml of dimethylformamide (DMF) are added slowly 24 mmol of the
compound obtained in the above stage dissolved in 120 ml of DMF. The
mixture is maintained at 120.degree. C. for 4 hours. After cooling,
dilution with water, extraction with ether, drying and evaporation, the
expected product is obtained.
Stage C: trans-1-Benzyl-3-chloromethyl-4-(2-hydroxyphenyl)pyrrolidine
hydrochloride
4.6 mmol of the compound obtained in the above stage are dissolved in 100
ml of chloroform. After sparging for 10 minutes with hydrogen chloride
gas, the reaction medium is brought to reflux and 13.8 mmol of thionyl
chloride are then added. The reflux is maintained until gaseous evolution
has ceased. After evaporation of the solvent, the residue is taken up in
ethanol and then evaporated. The expected product then precipitates in
ether.
Stage D:
trans-2-Benzyl-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole hydroc
hloride
2.95 mmol of the compound obtained in the above stage are dissolved in 100
ml of THF and 10 ml of hexamethylphosphorotriamide (HMPT). 4 ml of a 1.6M
solution of butyllithium in hexane are then added to the above mixture.
The mixture is kept stirring for 15 hours. After hydrolysis and
evaporation of the solvents, the residue is taken up in water and
extracted with ether. After drying and evaporation of the organic phases,
the expected product is obtained by purification of the residue by column
chromatography on silica, using a dichloromethane/methanol mixture (97/3)
as eluent. The base is salified in hydrochloric ethanol.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 71.63 6.68 4.64 11.75
found 71.31 6.61 4.70 12.04
______________________________________
EXAMPLE 2
trans-2-Benzyl-9-hydroxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le hydrochloride
Stage A: trans-1-Benzyl-3-hydroxymethyl-4-(2,6-dimethoxyphenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage A of Example 1, using methyl
[trans-1-benzyl-4-(2,6-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate,
described in Preparation B, as starting material.
Stage B: trans-1-Benzyl-3-chloromethyl-4-(2,6-dimethoxyphenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage C of Example 1.
Stage C: trans-1-Benzyl-3-chloromethyl-4-(2,6-dihydroxyphenyl)pyrrolidine
To 5.8 mmol of the compound obtained in the above stage, dissolved in 100
ml of dichloromethane, are added 29 ml of a 1M solution of boron
tribromide in dichloromethane. The mixture is maintained at reflux for 5
hours. After cooling, 77 ml of ethyl ether and then 200 ml of saturated
sodium hydrogen carbonate solution are added. After extraction with ether,
the organic phases are washed with saturated sodium hydrogen carbonate
solution, dried and evaporated. The expected product is obtained after
purification of the residue by column chromatography on silica, using a
cyclohexane/ethyl acetate mixture (80/20) as eluent.
Stage D:
trans-2-Benzyl-9-hydroxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrr
ole hydrochloride
The expected product is obtained according to the process described in
Stage D of Example 1.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.09 6.03 4.41 11.17
found 67.73 6.35 4.41 4.27
______________________________________
EXAMPLE 3
trans-2-Benzyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le hydrochloride
Stages A and B:
These stages are identical to Stages A and B of Example 2.
Stage C:
trans-1-Benzyl-3-chloromethyl-4-(2-hydroxy-6-methoxyphenyl)pyrrolidine
To 28.9 mmol of the compound obtained in the above stage, dissolved in 200
ml of dichloromethane, are added 57.8 ml of a 1M solution of boron
tribromide in dichloromethane. The reaction medium is maintained at reflux
for 45 minutes. After cooling and addition of 800 ml of water, the pH is
brought to 10. After extraction with dichloromethane, drying and
evaporation, the residue is purified by column chromatography on silica,
using dichloromethane as eluent. The expected product is obtained after
releasing with methanol and then with 1N sodium hydroxide.
Stage D:
trans-2-Benzyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrr
ole hydrochloride
To 9.3 mmol of sodium hydride in 20 ml of THF is added a solution
containing 7.8 mmol of the compound obtained in the above stage in 20 ml
of THF. The reaction medium is maintained at reflux for 3 hours and then
hydrolyzed. After extraction with ether, drying and evaporation, the
expected product is obtained by purification of the residue by column
chromatography on silica, using a dichloromethane/methanol mixture (95/5)
as eluent.
Elemental microanalysis
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.77 6.68 4.22 10.68
found 68.34 6.47 4.51 11.21
______________________________________
EXAMPLE 4
trans-9-Methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
2.2 mmol of the compound obtained in Example 3 in 100 ml of ethanol and 30
ml of water are hydrogenated for 1 hour at 45.degree. C. in the presence
of 70 mg of palladium-on-charcoal as catalyst. The expected product is
obtained after evaporation of the solvents.
Elemental microanalysis
______________________________________
C % H % N % Cl %
______________________________________
calculated 59.63 6.63 5.79 14.67
found 58.93 6.09 5.85 15.14
______________________________________
EXAMPLE 5
trans-2-Acetyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le
To 0.8 mmol of the compound obtained in Example 4 in 30 ml of chloroform
are successively added 1.66 mmol of triethylamine and then 0.8 mmol of
acetyl chloride. After stirring for one hour at room temperature, the
reaction medium is hydrolyzed. After extraction with chloroform, drying
and evaporation, the expected product is obtained after crystallization of
the residue from ethyl ether.
Elemental microanalysis:
______________________________________
C % H %
______________________________________
calculated 68.00 6.93
found 67.21 6.57
______________________________________
EXAMPLE 6
trans-2-Propyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le
To 3.3 mmol of the compound obtained in Example 4, dissolved in 20 ml of
acetonitrile and 10 ml of acetone, are successively added 6.6 mmol of
potassium carbonate and then 3.3 mmol of 1-bromopropane. The reaction
medium is maintained at reflux for 15 hours. After cooling, filtration,
hydrolysis and extraction with dichloromethane, the organic phases are
dried and then evaporated. The expected product is obtained after
purification of the residue by column chromatography on silica, using a
dichloromethane/methanol/aqueous ammonia mixture (90/10/0.5) as eluent.
The base thus obtained is salified in hydrochloric ethanol.
Melting point: 233.degree. C.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 63.48 7.81 4.94 12.45
found 63.53 7.86 4.84 12.74
______________________________________
EXAMPLE 7
trans-2-Allyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrol
To 3.3 mmol of the compound obtained in Example 4, dissolved in 30 ml of
chloroform, are successively added 6.6 mmol of triethylamine and then 3.3
mmol of allyl bromide. The reaction medium is maintained at reflux for one
hour and then hydrolyzed with 1N sodium hydroxide. After extraction with
chloroform, the organic phases are combined, dried and evaporated. The
expected product is obtained after purification of the residue by column
chromatography on silica, using a dichloromethane/methanol/aqueous ammonia
mixture (95/5/0.5) as eluent.
Elemental microanalysis:
______________________________________
C % H % N %
______________________________________
calculated 63.15 6.35 3.87
found 61.59 6.41 3.88
______________________________________
EXAMPLE 8
trans-2-[3-(4-Fluorobenzoylamino)ethyl]-9-methoxy-1,3,3a,4,9b-pentahydro-(1
)-benzopyrano[3,4-c]pyrrole
Stage A:
trans-2-Cyanomethyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c
]pyrrole
To 4.14 mmol of the compound obtained in Example 4, dissolved in 20 ml of
acetonitrile, are successively added 8.28 mmol of potassium carbonate and
then a solution containing 4.14 mmol of bromoacetonitrile in 20 ml of
acetonitrile. The reaction medium is maintained at reflux for 15 hours.
After cooling and filtration the filtrate is hydrolyzed and extracted with
dichloromethane. The organic phases are dried and evaporated, and the
expected product is obtained after purification of the residue by column
chromatography on silica, using a dichloromethane/methanol mixture (98/2)
as eluent.
Stage B:
trans-2-(2-Aminoethyl)-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,
4-c]pyrrole
1.5 mmol of the compound obtained in the above stage are added to a
solution containing 3 mmol of lithium aluminum hydride in 15 ml of THF at
5.degree. C. The reaction medium is stirred for 90 minutes at this
temperature. After addition of 0.17 ml of water, 0.25 ml of 2N sodium
hydroxide and then 0.46 ml of water, the medium is again stirred for 3
hours and then filtered. The solvents are evaporated off and the expected
product is obtained after purification of the residue by column
chromatography on silica, using a dichloromethane/methanol/aqueous ammonia
mixture (80/20/2) as eluent.
Stage C:
trans-2-[3-(4-Fluorobenzoylamino)ethyl]-9-methoxy-1,3,3a,4,9b-pentahydro-(
1)-benzopyrano[3,4-c]pyrrole
To 1 mmol of the compound obtained in the above stage, dissolved in 80 ml
of chloroform at 5.degree. C., are added 1 mmol of triethylamine and then,
after stirring for 15 minutes, 1 mmol of para-chlorobenzoyl chloride. The
reaction medium is maintained at 5.degree. C. for 90 minutes and then
hydrolyzed using 1N sodium hydroxide. After extraction with
dichloromethane, the organic phases are dried and evaporated, and the
expected product is obtained after purification of the residue by column
chromatography on silica. The base is then salified in hydrochloric
ethanol and the hydrochloride crystallizes from pentane.
Melting point: 202.degree. C.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 61.99 5.95 6.88 8.71
found 61.85 5.91 6.92 8.52
______________________________________
EXAMPLE 9
trans-2-Benzyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le hydrochloride
Stage A: trans-1-Benzyl-3-hydroxymethyl-4-(2,5-dimethoxyphenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage A of Example 1, starting with methyl
[trans-1-benzyl-4-(2,5-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate
described in Preparation C.
Stage B:
trans-1-Benzyl-3-hydroxymethyl-4-(2-hydroxy-5-methoxyphenyl)pyrrolidine
97 mmol of ethanethiol are added to a solution containing 97 mmol of sodium
hydride in 150 ml of DMF at 10.degree. C. After stirring for 15 minutes at
this temperature, 24 mmol of the compound obtained in Stage A are added
and the reaction medium is maintained at 120.degree. C. for 3 hours. After
cooling, hydrolysis, extraction with ether and then with dichloromethane,
the organic phases are combined, dried and evaporated. The expected
product is obtained after purification by column chromatography on silica,
using a dichloromethane/methanol mixture (95/5) as eluent.
Stage C:
trans-1-Benzyl-3-chloromethyl-4-(2-hydroxy-5-methoxyphenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage C of Example 1, starting with the compound obtained in the above
stage.
Stage D:
trans-2-Benzyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrr
ole hydrochloride
The expected product is obtained according to the process described in
Stage D of Example 1, starting with the compound obtained in the above
stage.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.77 6.68 4.22 10.68
found 68.34 6.67 4.22 10.56
______________________________________
EXAMPLE 10
trans-8-Methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
The expected product is obtained according to the process described in
Example 4, starting with the compound obtained in Example 9.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 59.63 6.67 5.79 14.62
found 59.58 6.60 5.77 14.30
______________________________________
EXAMPLE 11
trans-2-Propyl-8-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le hydrochloride
The expected product is obtained according to the process described in
Example 6, starting with the compound described in Example 10.
Chromatographic purification is performed using a dichloromethane/methanol
mixture (95/5) as eluent, and gives the hydrochloride.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 63.48 7.88 4.94 12.49
found 63.05 7.66 4.97 12.51
______________________________________
EXAMPLE 12
cis-2-Benzyl-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
Stage A: cis-1-Benzyl-3-hydroxyphenyl-4-(2-hydroxyphenyl)pyrrolidine
125 mmol of cis-2-benzyl-1,3,3a,9b-tetrahydrobenzopyrano[3,4-c]pyrrol-4-one
(described in Preparation D) are added to a heterogeneous solution
containing 310 mmol of lithium aluminum hydride in 800 ml of THF at
5.degree. C. The reaction medium is kept stirring for 3 hours at room
temperature and is then cooled to +10.degree. C. 120 ml of ethyl alcohol,
120 ml of water and then 40 ml of aqueous 40% sodium hydroxide solution
are successively added. After filtration of the salts, the filtrate is
washed with saturated sodium bicarbonate solution. The organic phase is
dried and, after evaporation, gives the expected product.
Stage B: cis-1-Benzyl-3-chloromethyl-4-(2-hydroxyphenyl)pyrrolidine
hydrochloride
The expected product is obtained according to the process described in
Stage C of Example 1, starting with the compound described in the above
stage.
Stage C: cis-2-Benzyl-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
The expected product is obtained according to the process described in
Stage D of Example 1, starting with the compound obtained in the above
stage.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 71.63 6.68 4.64 11.75
found 71.46 6.29 4.98 11.62
______________________________________
EXAMPLE 13
cis-1,3,3a,4,9b-Pentahydro-(1)-benzopyrano[3,4-c]pyrrole hydrochloride
The expected product is obtained according to the process described in
Example 4, starting with the compound obtained in Example 12.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 62.41 6.67 6.62 16.75
found 61.77 6.47 6.43 16.54
______________________________________
EXAMPLE 14
cis-2-Benzyl-9-hydroxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
Stage A: cis-1-Benzyl-3-hydroxymethyl-4-(2,6-dimethoxyphenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage A of Example 12, starting with methyl
[cis-1-benzyl-4-(2,6-dimethoxyphenyl)pyrrolidin-3-yl]carboxylate described
in Preparation E.
Stage B: cis-1-Benzyl-3-chloromethyl-4-(2,6-dimethoxyphenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage C of Example 1, starting with the compound described in the above
stage.
Stage C: cis-1-Benzyl-3-chloromethyl-4-(2,6-dihydrophenyl)pyrrolidine
hydrochloride
To 8.9 mmol of the compound obtained in the above stage, in 170 ml of
dichloromethane, are added 44.5 ml of a 1M solution of boron tribromide in
dichloromethane. The reaction medium is maintained at reflux for 8 hours
and then treated with concentrated sodium hydroxide for one hour. The
medium is then neutralized using hydrochloric acid. After extraction with
dichloromethane, the expected product is obtained after purification of
the residue-by column chromatography on silica, using a
dichloromethane/methanol mixture (95/5) as eluent.
Stage D:
cis-2-Benzyl-9-hydroxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrol
e hydrochloride
The expected product is obtained according to the process described in
Stage D of Example 1.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.03 6.34 4.41 4.26
found 67.43 6.50 4.38 10.66
______________________________________
EXAMPLE 15
cis-2-Benzyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
11.6 mmol of the compound obtained in Example 14, in 50 ml of DMF, are
added to a solution containing 14 mmol of sodium hydride in 50 ml of DMF.
After stirring for 30 minutes, 11.6 mmol of methyl iodide are added. After
1 hour at room temperature, followed by hydrolysis, the solvents are
evaporated off. The residue is then taken up in water. After extraction
with ether, drying and evaporation, the expected product is obtained after
purification of the residue by column chromatography on silica, using a
cyclohexane/ethyl acetate mixture (75/25) as eluent.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.77 6.68 4.22 10.68
found 68.66 4.48 4.45 10.97
______________________________________
EXAMPLE 16
cis-9-Methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
The expected product is obtained according to the process described in
Example 4, starting with the compound described in Example 15.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 59.63 6.67 5.79 14.67
found 59.97 6.69 5.93 13.87
______________________________________
EXAMPLE 17
cis-2-Acetyl-9-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
The expected product is obtained according to the process described in
Example 5, starting with the compound described in Example 16.
Elemental microanalysis
______________________________________
C % H % N %
______________________________________
calculated 68.00 6.93 5.68
found 67.89 6.94 5.49
______________________________________
EXAMPLE 18
trans-2-Benzyl-7-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrol
e hydrochloride
Stage A:
trans-1-Benzyl-3-hydroxymethyl-4-(2-methoxy-4-chlorophenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage A of Example 1, using methyl
[trans-1-benzyl-4-(2-methoxy-4-chlorophenyl)pyrrolidin-3-yl]carboxylate,
described in Preparation F, as starting material.
Stage B:
trans-1-Benzyl-3-hydroxymethyl-4-(2-hydroxy-4-chlorophenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage B of Example 9, starting with the compound obtained in the above
stage.
Stage C:
trans-1-Benzyl-3-chloromethyl-4-(2-hydroxy-4-chlorophenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage C of Example 1, starting with the compound obtained in the above
stage.
Stage D:
trans-2-Benzyl-7-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le hydrochloride
The expected product is obtained according to the process described in
Stage D of Example 3 (using two equivalents of sodium hydride), starting
with the compound obtained in the above stage.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 64.29 5.70 4.17 21.09
found 64.25 5.72 4.03 21.27
______________________________________
EXAMPLE 19
cis-2-[2-(Thiochroman-8-yloxy)ethyl]-1,3,3a,9b-pentahydro-(1)-benzopyrano[3
,4-c]pyrrole hydrochloride
To 4.7mmol of cis-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride, described in Example 13, in 50 ml of acetonitrile are added
9.4 mmol of potassium carbonate. After stirring for 15 min, 0.5 mmol of
potassium iodide and then 4.7 mmol of
1-chloro-2-(thiochroman-8-yloxy)ethane dissolved in 50 ml of acetonitrile
are successively added. The reaction medium is maintained at reflux for 24
hours and then evaporated, taken up in water, extracted with
dichloromethane and dried over magnesium sulfate before being filtered.
The solvents are evaporated off. The crude product is purified by column
chromatography on silica (eluent: CH.sub.2 Cl.sub.2 /MeOH: 97/3). The
product is then salified by a solution of HCl in ethanol.
Elemental microanalysis:
______________________________________
C % H % N % Cl % S %
______________________________________
calculated
65.41 6.49 3.47 8.78 7.94
found 65.08 6.31 3.58 8.23 8.23
______________________________________
EXAMPLE 20
cis-2-[(Pyrid-3-yl)aminocarbonyl]-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,
4-c]pyrrole hydrochloride
To 30 mmol of the product obtained in Example 16 in 50 ml of
dichloromethane is added 0.15 mmol of 3-pyridyl isocyanate. After stirring
for 48 hours, the product is filtered off and then chromatographed on a
column of silica (eluent: dichloromethane/methanol: 95/5). The product
obtained is salified using ethanolic hydrochloric acid solution.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 59.75 5.57 11.61
9.80
found 60.06 5.56 11.38
8.94
______________________________________
EXAMPLE 21
cis-2-Benzyl-7-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
Stage A:
cis-1-Benzyl-3-hydroxymethyl-4-(2-hydroxy-4-methoxyphenyl)pyrrolidine
To 230 mmol of lithium aluminum hydride in 800 ml of THF, under a nitrogen
atmosphere, are added 180 mmol of
cis-2-benzyl-7-methoxy-1,3,3a,9b-tetrahydrobenzopyrano
[3,4-c]pyrrol-4-one, described in Preparation G, at +5.degree. C. The
reaction medium is maintained at +10.degree. C. for one hour before being
hydrolyzed, and is filtered on Celite. The organic phase is dried and,
after evaporation, gives the expected product.
Stage B:
cis-2-Benzyl-7-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrol
e hydrochloride
To 93 mmol of the compound obtained in Stage A in 700 ml of tetrahydrofuran
(THF) are successively added 93 mmol of diethyl azodicarboxylate and 93
mmol of triphenylphosphine. The reaction medium is stirred for 3 hours at
room temperature and the solvents are then evaporated off. The crude
product is purified by column chromatography on silica (eluent:
cyclohexane/ethyl acetate: 70/30). The product is salified using a
solution of hydrochloric acid in ethanol.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.77 6.68 4.22 10.68
found 69.01 6.74 4.16 10.70
______________________________________
EXAMPLE 22
trans-2-Benzyl-7-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le hydrochloride
Stage A: trans-1-Benzyl-3-hydroxymethyl-4-(2,4-dimethoxyphenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage A of the Example 1, using the compound described in Preparation H.
Stage B:
trans-1-Benzyl-3-hydroxymethyl-4-(2-hydroxy-4-methoxyphenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage B of Example 1, using the compound obtained in the above stage as
starting material.
Stage C:
trans-2-Benzyl-7-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrr
ole hydrochloride
The expected product is obtained according to the process described in
Stage B of Example 21, starting with the compound obtained in the above
stage.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.77 6.68 4.22 10.68
found 68.44 6.59 4.49 10.77
______________________________________
EXAMPLE 23
trans-2-Benzyl-6-methoxy-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrro
le hydrochloride
The expected product is obtained according to Stages A, B and C of Example
23, starting with the compound obtained from Preparation I.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.77 6.68 4.22 10.68
found 67.93 6.66 4.10 10.55
______________________________________
EXAMPLE 24
cis-2-Benzyl-8-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
Stage A:
cis-1-Benzyl-3-hydroxymethyl-4-(2-hydroxy-5-chlorophenyl)pyrrolidine
The expected product is obtained according to the process described in
Stage A of Example 12, using the compound described in Preparation J as
starting material.
Stage B:
cis-2-Benzyl-8-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
The expected product is obtained according to the process described in
Stage B of Example 21, starting with the compound obtained in the above
stage.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 64.29 5.70 4.17 21.09
found 64.82 5.82 4.19 20.81
______________________________________
EXAMPLE 25
trans-2-Benzyl-8-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrol
e hydrochloride
The expected product is obtained according to Stages A, B and C of Example
22, starting with the compound obtained from Preparation K.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 64.29 5.70 4.17 21.09
found 64.01 6.01 4.22 21.05
______________________________________
EXAMPLE 26
cis-2-Benzyl-6-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
The expected product is prepared according to Stage A of Example 12 and
then Stage B of Example 21, starting with the compound obtained in
Preparation L.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 64.29 5.70 4.17 21.09
found 63.72 5.59 4.26 24.16
______________________________________
EXAMPLE 27
trans-2-Benzyl-6-chloro-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrol
e hydrochloride
The expected product is obtained according to Stages A, B and C of Example
1 and then according to Stage D of Example 3, starting with the compound
obtained in Preparation M.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 64.29 5.70 4.17 21.09
found 64.22 5.45 4.01 21.47
______________________________________
EXAMPLE 28
trans-2-Benzyl-8-bromo-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
The expected product is obtained according to Stages A, B and C of Example
1 followed by Stage D of Example 3, starting with the compound obtained in
Preparation N.
Elemental microanalysis:
______________________________________
C % H % N % Br % Cl %
______________________________________
calculated
56.79 5.03 3.68 20.99
9.31
found 57.14 5.19 3.48 20.00
9.18
______________________________________
EXAMPLE 29
trans-2-Benzyl-8-cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
9 mmol of the compound of Example 18 are dissolved in 10.4 ml of
dimethylformamide. 5 mmol of zinc cyanide and 0.3 mmol of
tetrakis(triphenylphosphine)palladium are then added. The reaction medium
is maintained at 80.degree. C. for 6 hours. After cooling, 30 ml of
toluene are added and the mixture is washed with twice 20 ml of 2M aqueous
ammonia solution and then using saturated sodium chloride solution. After
evaporation of the solvents, the crude product is salified using a
solution of hydrochloric acid in ethanol.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 69.83 5.86 8.57 10.85
found 69.41 5.77 8.53 10.83
______________________________________
EXAMPLE 30
trans-8-Cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
17.2 mmol of the compound obtained in Example 29 in 130 ml of ethanol and
40 ml of water are hydrogenated for 24 hours at 40.degree. C. in the
presence of 500 mg of palladium-on-charcoal as catalyst. After evaporation
of the solvents, the expected product is obtained.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 60.89 5.54 11.83
14.98
found 60.44 5.52 11.45
14.26
______________________________________
EXAMPLE 31
trans-2-Propyl-8-cyano-1,3,3a,4,9b-pentahydro-(1)-benzopyrano[3,4-c]pyrrole
hydrochloride
The compound obtained in Example 30 is treated according to the procedure
described for Example 6.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 64.63 6.87 10.05
12.72
found 63.93 6.78 9.53
12.21
______________________________________
EXAMPLE 32
trans-2-Benzyl-1,2,3,3a,4,11c-hexahydro-5-oxa-2-aza-cyclopenta[c]phenanthre
ne hydrochloride
The expected product is obtained according to Stages A, B and C of Example
1 followed by Stage D of Example 3, starting with the compound obtained in
Preparation O.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 75.10 6.30 3.98 10.08
found 74.51 6.25 4.16 10.02
______________________________________
EXAMPLE 33
trans-1,2,3,3a,4,11c-Hexahydro-5-oxa-2-aza-cyclopenta[c]phenanthrene
hydrochloride
The product obtained in Example 32 is treated according to the procedure of
Example 30.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.83 6.16 5.35 13.54
found 68.49 6.25 4.99 13.47
______________________________________
EXAMPLE 34
trans-16-Benzyl-12,13,14,15,16,17-hexahydro-11-oxa-16-aza-cyclopenta[a]phen
anthrene hydrochloride
The expected product is obtained according to Stage A of Example 1 and then
treated according to the procedures described in Stage C of Example 2 and
Stage B of Example 21, starting with the compound of Preparation P.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 75.10 6.30 3.98 10.08
found 74.89 6.30 3.93 10.19
______________________________________
EXAMPLE 35
cis-16-Benzyl-12,13,14,15,16,17-hexahydro-11-oxa-16-aza-cyclopenta[a]phenan
threne hydrochloride
The expected product is obtained according to Stages A and B of Example 21,
starting with the compound obtained in Preparation Q.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 75.10 6.30 3.98 10.08
found 74.53 6.38 3.85 10.02
______________________________________
EXAMPLE 36
cis-12,13,14,15,16,17-Hexahydro-11-oxa-16-aza-cyclopenta[a]phenanthrene
hydrochloride
The expected product is obtained according to the process described for
Example 30, starting with the compound of Example 35.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.83 6.16 5.35 13.54
found 68.41 6.22 5.56 13.46
______________________________________
EXAMPLE 37
cis-2-Benzyl-1,2,3,3a,4,11c-hexahydro-5-oxa-2-aza-cyclopenta[c]phenanthrene
hydrochloride
The expected product is obtained according to Stages A and B of Example 21,
starting with the compound obtained in Preparation R.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 75.10 6.30 3.98 10.08
found 75.13 6.30 4.01 9.88
______________________________________
EXAMPLE 38
cis-1,2,3,3a,4,11c-Hexahydro-5-oxa-2-aza-cyclopenta[c]phenanthrene
hydrochloride
The expected product is obtained according to the process described for
Example 30, starting with the compound of Example 37.
Elemental microanalysis:
______________________________________
C % H % N % Cl %
______________________________________
calculated 68.83 6.16 5.35 13.54
found 68.25 6.11 5.43 13.19
______________________________________
Pharmacological Study of the Compounds of the Invention
EXAMPLE 39
Measurement of the in vitro affinity for the 5-HT.sub.2C and 5-HT.sub.2A
receptors
Methods
The procedures described for the studies of the binding to the 5-HT.sub.2A
and 5-HT.sub.2C receptors are exactly those described by H. Canton et al.
(Eur. J. Pharmacol., 191, 93, 1990) and M. J. Millan et al. (J. Pharmacol.
Exp. Ther., 262, 451-463, 1992). For 5-HT.sub.2A : rat frontal
cortex/[.sup.3 H]-ketanserin (1.0 nM). For 5-HT.sub.2C : pig cerebral
plexus/[.sup.3 H]-mesulergine (1.0 nM). The 50% inhibitory doses
(ID.sub.50) are determined by regression analysis and the pKi values are
calculated as follows:
##EQU1##
[L]=concentration of the Kd-Kd=dissociation constant Results
The results obtained with the reference compounds and the compounds of the
invention are combined in the table below.
SB 200,646 showed a modest affinity for the 5-HT.sub.2C receptors of the
order of 200 nM and had only a weak affinity for the 5-HT.sub.2A sites.
Its selectivity is thus 6 for the 5-HT.sub.2C sites. On the other hand,
MDL 100,907 showed a very considerable selectivity of the order of 200 for
the 5-HT.sub.2A receptors, for which it has a very strong affinity.
The compounds of the invention have a greater affinity for the 5-HT.sub.2C
receptors than the reference compound SB 200,646. Furthermore, they have a
better selectivity for the 5-HT.sub.2C receptors with respect to the
5-HT.sub.2A receptors.
There may more particularly be mentioned the compounds of Examples 19 and
20, which are 9 and 14 times more powerful antagonists respectively than
the reference compound SB 200,646, and the compounds of Examples 6 and 7,
which have a selectivity which is twice that of the reference compound SB
200,646.
______________________________________
5-HT.sub.2C
5-HT.sub.2A
5-HT.sub.2A /5-HT.sub.2C
Compound Ki (nM) Ki (nM) affinity ratio
______________________________________
Example 2 195 490 2.5
Example 3 48 269 5.6
Example 4 431 3468 8.0
Example 6 104 1738 16.7
Example 7 120 1820 15.2
Example 8 107 95 0.9
Example 9 468 1097 2.3
Example 10 2188 >10000 >4.8
Example 11 4074 >10000 >2.3
Example 12 832 3549 4.3
Example 13 3090 >10000 >3.33
Example 14 218.8 1096 5.00
Example 15 36.3 389.0 10.7
Example 16 263 3311 12.6
Example 18 871 1867 2.1
Example 19 22 155 7.0
Example 20 14.4 102 7.1
Example 21 871 617 0.7
Example 22 478 170 3.6
Example 24 38 107 2.8
Example 33 51 107 2.1
Example 34 776 1479 1.9
Example 35 331 955 2.9
Example 36 25.7 257 10
Example 37 155 1349 8.7
Example 38 22.9 97.7 4.3
SB 200,646 204.0 1318 6.5
MDL 100,907
107.2 0.59 0.006
______________________________________
Each value represents the average of two to four determinations.
EXAMPLE 40
Pharmaceutical composition
______________________________________
Formula for the preparation of 1000 tablets
containing a 10 mg dose:
______________________________________
Compound of Example 16
10 g
Hydroxypropylcellulose
2 g
Wheat starch 10 g
Lactose 100 g
Magnesium stearate 3 g
Talc 3 g
______________________________________
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